1. Field of the Invention
The present invention relates to a method and apparatus for quantitatively evaluating a kidney with respect to normal functioning, the effect of diuresis, and to detect any malfunction, including but not limited to hydronephrosis.
2. Prior Art
The major function of the kidney is to maintain body fluid and electrolyte homeostasis by filtering waste from the plasma and excreting the end products. Fluid homeostasis largely depends on the corticomedullary extracellular sodium concentration gradient. This gradient is maintained by a countercurrent mechanism, and serves as the driving force behind the reabsorption of water from the filtrate back into the plasma. Recently, based on a mathematical model of volume and solute microvascular exchange in the renal medulla, an exponential increase of sodium along the corticomedullary axis was hypothesized, Edwards A, Delong M J and Pallone T L. Interstitial water and solute recovery by inner medullary vasa recta. Am. J. Physiol. Renal Physiol. 278: F257–F269, 2000. This model supported the earlier electron microprobe data obtained by Koepsell et al. Measurements of exponential gradients of sodium and chlorine in the rat kidney medulla using electron microprobe. Pflugers Arch. 350: 167–184, 1974. However, the sodium concentration in the papilla reported by the latter authors was significantly higher than that determined in numerous other studies Azar S, Tobian L and Ishii M. Prolonged water diuresis affecting solutes and interstitial cells of renal papilla. Am. J. Physiol. 221: 75–79, 1971; Bengele H H, Mathias R S, Perkins J H and Alexander E A. Urinary concentrating defect in aged rat. Am. J. Physiol. 240: F147–F150, 1981; Buerkert J, Martin D, Prasad J and Trigg D. Role of deep nephrons and the terminal collecting duct in mannitol-induced diuresis. Am. J. Physiol. 240: F411–F422, 1981; Gennari F J, Johns C, Caflisch C R and Cortell S. Dissociation of saline-induced natiuresis from urea washout in the rat. Am. J. Physiol. 241: F250–F256, 1981; Jamison R L. The renal concentrating mechanism: micropuncture studies of the renal medulla. Fed. Proc. 42: 2392–2397, 1983; Martinez-Maldonado M, Eknoyan G and Suki W N. Influence of volume expansion on renal diluting capacity in the rat. Clin. Sci. Mol. Med. 46: 331–345, 1974; Pallone T L, Yagil Y and Jamison R L. Effect of small-solute gradients on transcapillary fluid movement in renal inner medulla. Am. J. Physiol. 257: F547–F553, 1989; Valtin H. Sequensration of urea and non urea solutes in renal tissues of rats with hereditary hypothalamic diabetes insipidus: effect of vasopressin and dehydration on countercurrent mechanism. J. Clin. Invest. 45: 337–345, 1966; and Wolff S D, Eng J, Berkowitz B A, James S and Balaban R S. Sodium-23 nuclear magnetic resonance imaging of the rabbit kidney in vivo. Am. J. Physiol. 258: F1125–F1131, 1990.
It is generally known that the sodium gradient is modified by administrating diuretic agents such as furosemide and mannitol, Suki W N, Stinebaugh B J, Frommer J P and Eknoyan G. Physiology of diuretic action. In: The kidney; phydiology and pathophysiology., edited by Seldin D W and Giebisch G. New York: Raven Press, 1985, p. 2127–2162. Furosemide, a loop diuretic agent, exerts its influence by blocking the Na+/2Cl−/K+ co-transporter located in the apical membrane of the thick segment of the medullar ascending limb. This co-transporter, together with the Na−/K+/ATPase pump in the basal membrane, extrudes sodium from the tubule to the interstitium. Thus, furosemide reduces the corticomedullary sodium gradient by inhibiting sodium reabsorption in the thick ascending limb, Puscheft J B. Pharmacological classification and renal actions of diuretics. Cardiology 84: 4–13, 1994. Mannitol, the osmotic diuretic agent most widely employed in the clinic, induces a decrease in renal vascular resistance, and an increase in extracellular fluid volume. These induced changes serve to amplify the medullar blood flow that “washes out” the excess sodium in the inner medulla, Better O S, Rubinstein I, Winaver J M and Knochel J P. Mannitol therapy revisited (1940–1997). Kidney Int. 51: 886–894, 1997. Although these two diuretics work are different, both decrease the sodium concentration in the inner medulla, Fraser A G, Cowie J F, Lambie A T and Robson J S. The effects of furosemide on the osmolality of the urine and the composition of the renal tissue. J. Pharmacol. exp. Ther. 158: 457–486, 1967; and Lote C J. Principle of renal physiology. London: Chapman & Hall, 1994.
Previous studies of sodium distribution in the kidney, and the diminution of the sodium concentration gradient following administration of furosemide and mannitol, Better O S, Rubinstein I, Winaver J M and Knochel J P. Mannitol therapy revisited (1940–1997). Kidney Int. 51: 886–894, 1997; and Puscheft J B. Pharmacological classification and renal actions of diuretics. Cardiology 84: 4–13, 1994; applied micropuncture, Buerkert J, Martin D, Prasad J and Trigg D. Role of deep nephrons and the terminal collecting duct in mannitol-induced diuresis. Am. J. Physiol. 240: F411–F422, 1981; and Jamison R L. The analytic methods used for the renal concentrating mechanism include: micropuncture studies of the renal medulla. Fed. Proc. 42: 2392–2397, 1983; radioautographic, Krakusin J S and Jennings R B. Radioautographic localization of 22-Na in the rat kidney. A.M.A. Arc. Pathol. 59: 471–486, 1955; and slice section, Bengele H H, Mathias R S, Perkins J H and Alexander E A. Urinary concentrating defect in aged rat. Am. J. Physiol. 240: F147–F150, 1981; and Atherton J C, Hai M A and Thomas S. The time course of changes in renal tissue composition during mannitol diuresis in the rat. J. Physiol. 197: 411–428, 1968. As these methods are invasive, it is of utmost importance to develop non-invasive means to monitor in vivo the spatial distribution of sodium in the kidney.
Obstructive uropathy caused by ureteric obstruction is one of the most common diseases of the urinary tract. Associated with this disorder are morphological changes of the urinary tract including a distended pelvic region with a flattened papilla, atrophy of renal parenchyma and hydroureter, Chuang, Y. H., W. L. Chuang, S. P. Huang, K. M. Liu, and C. H. Huang. The temporal relationship between the severity of hydroureter and the dynamic change of obstructed ureter in the rat model. Br. J. Urol. 76: 303–310, 1995. The extent of renal damage depends on the degree and duration of the obstruction, Leahy, A. L., P. C. Ryan, G. M. McEnttee, A. C. Nelson, and J. M. Fitzpatrick. renal injury and recovery in partial ureteric obstruction. J. Urol. 142: 199–203, 1989. In previous studies of uropathy in an animal model, using ureter ligation, changes were demonstrated in the morphology, haemodynamics and renal function of the hydronephrotic kidneys, Josephson, S., A. C. Ericson, and M. Sjoquist. Experimental obstructive hydronephrosis in newborn rats. J. Urol. 134: 391–395, 1985; Leahy, A. L., P. C. Ryan, G. M. McEnttee, A. C. Nelson, and J. M. Fitzpatrick. renal injury and recovery in partial ureteric obstruction. J. Urol. 142: 199–203, 1989; and Morsing, P., and E. G. Persson. Tubuloglomerular feedback in obstructive uropathy. Kidney Int. 39: S110–S114, 1991.
The most common techniques for monitoring obstructive pathology of the urinary tract have been intravenous urography and sonography, Brown, D. F., C. L. Rosen, and R. E. Wolfe. Renal ultrasonography. Emerg. Med. Clin. North. Am. 15: 877–893, 1997; Mustonen, S., I. O. Ala-Houala, P. Vehkalahti, p. Laippala, and T. L. J. Tammela. Kidney ultrasound and doppler ultrasound finding during and after acute urinary retention. Eur. J. Ultrasound 12: 189–196, 2001. Urography uses ionized radiation and i.v. injection of a contrast agent that may be harmful due to the potential nephrotoxicity of the contrast media, Katzberg, R. W. Urography into the 21st century: new contrast media, renal hendling, imaging characteristics, and nephrotoxicity. radiology 204: 297–312, 1997. Therefore patients with decreased renal function cannot be evaluated with CT. Although sonography is relatively sensitive for diagnosing obstruction, this method has difficulties in determining the extent of obstruction and cannot assess renal function, Brown, D. F., C. L. Rosen, and R. E. Wolfe. Renal ultrasonography. Emerg. Med. Clin. North. Am. 15: 877–893, 1997; and Rosi, P., G. Virgili, S. M. Di Stasi, A. Giurioli, B. Sensi, G. Vespasiani, and M. Porena. Diuretic ultrasound. A non-invasive technique for the assessment of upper tract obstruction. Br. J. Urol. 65: 566–569, 1990. More recently non-enhanced helical CT and dynamic contrast enhanced MRI using GdDTPA as a contrast agent has been evaluated in patients with suspected urinary obstruction, Chen, M. Y. M., and R. J. Zagoria. Can noncontrast helical computed tomography replace intravenous urography for evaluation of patients with acute urinary tract colic. J. Emerg. Med. 17: 299–303, 1999; and Wen, J. G., Y. Chen, S. Ringgaard, J. Frokiaer, T. M. Jorgensen, H. Stodkilde-Jorgensen, and J. C. Djurhuus. Evaluation of renal function in normal and hydronephrotic kidneys in rats using gadolinium diethylenetetramine-pentaacetic acid enhanced dynamic magnetic resonance imaging. J. Urol. 163: 1264–1270, 2000. However both methods do not provide detailed information about renal function in cases of complete obstruction. Consequently, it is up of important to look for a non-invasive and safe method for assessing the functionality of the obstruct kidney.
One of the key functions of the kidney is to maintain fluid homeostasis. This function depends on the sodium and urea concentration gradient between the cortex and the medulla. This gradient, achieved by the countercurrent mechanism, serves as a driving force for reabsorbing water from the filtrate back into the plasma, Jamison, R. L., and W. Kriz. Urinary concentrating Mechanism. New York Oxford: Oxford University Press, Inc., 1982. It has been suggested, at least on a quantitative basis that MRI of the sodium nucleus could provide a unique, non-invasive tool for monitoring renal function by mapping directly the sodium spatial distribution, Maeda, M., Y. Seo, M. Murakami, S. Kuki, H. Watari, S. Iwasaki, and H. Uchida. Sodium imaging of the kidney in the Guinea pig at 2.1 T, following arterial, venous, and ureteral ligation. Magn. Reson. Med. 16: 361–367, 1990; and Ra, J. B., S. K. Hilal, C. H. Oh, and I. K. Mun. In vivo magnetic resonance imaging of sodium in the human body. Magn. Reson. Med. 7: 11–22, 1988. Variations in the sodium distribution in the obstructed kidney may relate to the extent of kidney obstruction. Previous 23Na MRI of the kidneys in rodents has demonstrated qualitatively the capacity of this method to detect the sodium gradient and to monitor changes in this gradient as a result of saline infusion, Bansal, N., and V. Seshan. Three-dimensional triple quantum filtered 23-Na imaging of rabbit kidney with weighted signal averaging. J. Magn. Reson. Imag. 5: 761–767, 1995; Wolff, S. D., C. Eng, and R. S. Balaban. NMR studies of renal phosphate metabolites in vivo: effects of hydration and dehydration. Am. J. Physiol. 255: F581–F589, 1988; and Wolff, S. D., J. Eng, B. A. Berkowitz, S. James, and R. S. Balaban. Sodium-23 nuclear magnetic resonance imaging of the rabbit kidney in vivo. Am. J. Physiol. 258: F1125–F1131, 1990.